Chemistry Reference
In-Depth Information
7
Telomeres and Telomerase: Potential
Targets for Platinum Complexes
Isabelle Ourliac - Garnier , Razan Charif and Sophie Bombard
7.1 Function of Telomeres
Telomeres are nucleoprotein structures that protect the very end of linear chromo-
somes. Telomeric DNA consists of tandemly repeated G-rich sequences of DNA,
which differ from one species to another, being (TTAGGG)
n
in humans. These
sequences of about 4-10 kbp protrude at the 3
extremity by a single strand of the
G-rich sequence of about 50 to 200 bases. Firstly, telomeres preserve the stability
and the structural integrity of chromosomes;
1 - 4
indeed, telomere dysfunction leads
to chromosome instability and abnormalities, senescence or apoptosis, and repre-
sents potentially the most widespread cause of genome instability in cancer.
5
So,
concretely, telomeres avoid end-to-end fusion of chromosomes by preventing the
chromosomes ends from being recognised as DNA double-strand breaks (DSB) and
consequently from being repaired.
6
Secondly, telomeres preserve the genome integ-
rity by protecting chromosomes from a loss of genetic information due to the 'end
replication problem': a progressive erosion of the 5
′
extremity of each chromosome
that happens at each round of replication.
7 - 10
Indeed, DNA replication involves
RNA primers, named Okazaki fragments, which are necessary for DNA synthesis
from the 5
′
extremities. The last replication fork is supposed to be subtelo-
meric, consequently, telomeric DNA is replicated unidirectionally and the G-rich
strand is synthesized discontinuously, whereas the C-rich one is replicated con-
tinuously (Figure 7.1). Then, conventional DNA polymerases replace Okazaki
′
to the 3
′
